Circulating Inflammatory Cytokines and Female Reproductive Diseases: A Mendelian Randomization Analysis

Extensive studies have provided considerable evidence suggesting the role of inflammation in the development of female reproductive diseases. However, causality has not been established.

To explore whether genetically determined circulating levels of cytokines are causally associated with female reproductive diseases and discover potential novel drug targets for these diseases.

Instrumental variables (IVs) for 47 circulating cytokines were obtained from a genome-wide association study (GWAS) meta-analysis of 31 112 European individuals. Protein quantitative trait loci and expression quantitative trait loci close to genes served as our IVs. Summary data of 9 female reproductive diseases were mainly derived from GWAS meta-analysis of the UK biobank and FinnGen. We elevated the association using the Wald ratio or inverse variance-weighted Mendelian randomization (MR) with subsequent assessments for MR assumptions in several sensitivity and colocalization analyses. We consider a false discovery rate <0.05 as statistical significance in MR analyses. Replication studies were conducted for further validation, and phenome-wide association studies were designed to explore potential side effects.

Our results indicated that high levels of macrophage colony-stimulating factor (MCSF), growth-regulated oncogene-alpha (GROα), and soluble intercellular adhesion molecule-1 were associated with increased risks of endometriosis, female infertility, and pre-eclampsia, respectively. High platelet-derived growth factor-BB (PDGF-BB) levels that reduced the risk of ovarian aging were also supported. Replication analysis supported the relationship between GROα and female infertility, and between MCSF and endometriosis.

We identified 4 correlated pairs that implied potential protein drug targets. Notably, we preferred highlighting the value of PDGF-BB as a drug target for ovarian aging, and MCSF as a drug target for endometriosis.